rs1994798

chr1-11794698-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005957.5(MTHFR):c.1166+31C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,613,318 control chromosomes in the GnomAD database, including 280,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24790 hom., cov: 32)
  • Exomes 𝑓: 0.59 (256165 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.42

Genes affected

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-11794698-G-A is Benign according to our data. Variant chr1-11794698-G-A is described in ClinVar as [Benign]. Clinvar id is 1177042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11794698-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.1166+31C>T		intron_variant		ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.1166+31C>T		intron_variant		1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85364 AN: 151888 Hom.: 24771 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.563

GnomAD3 exomes AF: 0.607 AC: 152736 AN: 251438 Hom.: 47927 AF XY: 0.599 AC XY: 81383 AN XY: 135898

Gnomad AFR exome AF: 0.433

Gnomad AMR exome AF: 0.773

Gnomad ASJ exome AF: 0.610

Gnomad EAS exome AF: 0.760

Gnomad SAS exome AF: 0.469

Gnomad FIN exome AF: 0.645

Gnomad NFE exome AF: 0.588

Gnomad OTH exome AF: 0.602

GnomAD4 exome AF: 0.588 AC: 859672 AN: 1461312 Hom.: 256165 Cov.: 49 AF XY: 0.584 AC XY: 424900 AN XY: 727012

Gnomad4 AFR exome AF: 0.435

Gnomad4 AMR exome AF: 0.761

Gnomad4 ASJ exome AF: 0.614

Gnomad4 EAS exome AF: 0.774

Gnomad4 SAS exome AF: 0.469

Gnomad4 FIN exome AF: 0.650

Gnomad4 NFE exome AF: 0.586

Gnomad4 OTH exome AF: 0.581

GnomAD4 genome AF: 0.562 AC: 85425 AN: 152006 Hom.: 24790 Cov.: 32 AF XY: 0.565 AC XY: 41967 AN XY: 74274

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.688

Gnomad4 ASJ AF: 0.617

Gnomad4 EAS AF: 0.759

Gnomad4 SAS AF: 0.483

Gnomad4 FIN AF: 0.640

Gnomad4 NFE AF: 0.586

Gnomad4 OTH AF: 0.562

Alfa AF: 0.574 Hom.: 5257

Bravo AF: 0.564

Asia WGS AF: 0.617 AC: 2147 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.023
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1994798; hg19: chr1-11854755; COSMIC: COSV64877997; COSMIC: COSV64877997;